Process for the preparation of phenyl pyrazole compounds

ABSTRACT

A process for the preparation of compound (III) which comprises the reaction between a compound of general formula (V) and dicyano acetylene (IV), said reaction carried out in the presence of water (IV), (V), (III) wherein R is selected from CF 3 , or C 1  to C 6  alkyl M is an alkaline or alkaline-earth metal or silver

The present invention relates to a process for preparing pesticidalintermediates, and to novel 2-arylhydrazono succinonitrile compounds andto 2-arylhydrazino sccinonitrile compounds.

European Patent Publication Nos. 0295117 and 0234119 describe thepesticidally active phenylpyrazole compounds and of5-amino-1-aryl-3-cyanopyrazole intermediate compounds used in theirsynthesis. Various methods for preparing these compounds are known, inparticular through various intermediate compounds. European Patent No.0966445 discloses a process for the preparation of a pyrazole compound,formula (II) which is then used to prepare a trifluoromethyl sulfinylderivative, generally known as fipronil. The process is as shown in thereaction scheme below, starting from an aryl-hydrazine, formula (1):

Unfortunately this process does not give a direct access to fipronilderivatives, and still requires a further sulphenylation step.

We have now found a method that gives a direct access to sulphenylatedderivatives of pyrazole (II).

Accordingly, the present invention provides a process for thepreparation of compound (III) which comprises the reaction between acompound of general formula (V) and dicyano acetylene of formula (IV),said reaction carried out in the presence of water

wherein R is selected from CF₃, or C₁ to C₆ alkyl; and

-   -   M is silver or an alkaline or alkaline-earth metal

The preferred compound of formula (V) is when R is trifluoro methyl(CF₃) and M is silver.

The process of the present invention may be carried out in the presenceof a solvent. The solvent is preferably an organic solvent that ismiscible with water. Suitable solvents include acetone andtetrahydrofuran.

The process may be carried out at a temperature of from −100 to +50° C.,preferably from −80 to +20° C. Concentration of the reactants may befrom 0.01 to 5 moles per liter of solvent

The molar ratio of dicyano acetylene to compound of formula (V) is from5:1 to 1:5. the preferred molar ratio is 1:1.

When R of compound (V) is CF3, the resulting compound III is a novelcompound and thus according to another aspect of the present invention,there is provided a novel compound (III) wherein R is CF₃

Compound of formula (III) may be used to prepare a known and keyintermediate compound of fipronil and according to a further aspect ofthe present invention there is provided a process for the preparation ofcompound (VII) which comprises a first step of reaction of an arylhydrazine of compound (I) with a compound of general formula (III) toproduce an intermediate compound of general formula (VI); and a secondstep which comprises the oxidation of compound (VI),

wherein R is selected from CF₃, or C₁ to C₆ alkyl;

Compound of formula (III) is as defined above and may be used in theform of the cis-isomer maleonitrile or the trans isomer fumaronitrile.Optionally a mixture of both isomers may be used. Arylhydraines offormula (I) are known or may be prepared by known methods.

The preferred compounds of formula (VI) have the same values of R as forcompounds of formula (III). Most preferably, compound of formula (VI) is1-trifluoromethyl thio 2-(2,6-dichloro-4-trifluoromethylphenylhydrazino) succinonitrile.

The first step of the process may be carried out in the presence of asolvent Suitable solvents include polar solvents such astetrahydrofurane, N-methylpyrrolidone, N,N-dimethylformamide ordimethylsulphoxide. The reaction may alternatively be carried out in theabsence of a solvent by heating a mixture of the two reactants, namelycompounds of formula (III) and (I).

The first step of the process may also be carried out in the presence ofa catalyst such as a tetra-alkylammonium salt for exampleN-benzyltrimethylammonium hydroxide, or alanine.

The reaction temperature in the first step of the process may be from 0to 150° C., preferably from 20 to 100° C.

The reaction may be carried out using a molar ratio of a compound offormula (II) to a compound of formula (I) of from 1:10 to 10:1,preferably from 1:1 to 5:1, especially from 1.1 to 1.

When R of compound (VI) is CF3, the resulting compound (VI) is a novelcompound and thus according to another aspect of the present invention,there is provided a novel compound (VI) wherein R is CF₃

Compounds of formula (VI) may be obtained as a mixture of syn and antiisomers and all such forms are embraced by the present invention.

The second step of the process comprises the oxidation of compound offormula (VI) to provide a hydrazone compound. Suitable oxidants for usein the second step include quinones such as benzoquinone, peroxides suchas hydrogen peroxide, hypohalites such as sodium hypochlorite, or analkali metal hydroxide such as sodium hydroxide in the presence of airor preferably a metal salt or oxide, for example, cupric chloride ormercuric oxide.

The oxidation reaction may be carried out in the presence of a solventSolvents suitable include aromatic halogenated or non-halogenatedhydrocarbons such as toluene or chlorobenzene, nitrites such asacetonitrile or amides such as N,N-dimethylformamide.

The oxidation step may be carried out at a temperature of from 20 to150° C., preferably from 50 to 100° C.

The aforementioned oxidation reaction may be merged with a spontaneouscyclisation of the intermediate hydrazone to produce the correspondingPyrazole

The present invention will now be illustrated with reference to thefollowing examples:

EXAMPLE 1 Preparation of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl) pyrazole

Hydrazine (290 miligrams, 1.2 mmol) was added to a solution of dicyanoacetylene (84 mg, 1.1 mmol) in chloroform (2 ml). The mixture wasstirred for 30 minutes at ambient temperature then heated to 50° C. for3 hours. Purification by flash chromatography on silica gel andcrystallisation from dichloromethane/hexane provided a white solid (316mg, 89%) which was recrystallised in a mixture of hexane/toluene (ratio2/1) to give the title compound (288 mg, 81% yield).

EXAMPLE 2 Preparation of 1,2-Dicyano-(trifluoromethylthio)ethene

A solution of CF₃SAg (836 mg; 4 mmol) in 2 ml of acetone chilled to −78°C. under argon was added to dicyanoacetylene (305 mg, 4 mmol) and water(85 mg) in 4 ml of acetone. The resulting mixture was shaken for 12hours. The mixture was allowed to reach 20° C. Purification by flashchromatography on silica gel and crystallization fromdichloromethane/hexane provided a mixture of the two isomers of thetitle compound (275 mg, 39% yield) in the form of a brown oil.

EXAMPLE 3 Preparation of1-(2,6-dichloro-4-trifluoromethylphenylhydrazono)1,2-dicyano-2-trifluoromethylthio ethane

A mixture of 1,2-Dicyano-1-(trirluoromethylthio)ethene (275 mg; 1.5mmol), obtained in Example 2, hydrazine (378 mg; 1.5 mmol) and 6 ml oftetrahydrofuran was stirred at ambient temperature for 24 hours.Purification by flash chromatography on silica gel and crystallisationfrom dichloromethane/hexane gave a light brown solid of the titleproduct (442 mg, 67% yield) in a 60/40 mix of the two isomers. The mainisomer was dissolved in chloroform and isolated after suspending in 5 mlof CHCL3, filtering and washing (80 mg, 12% yield).

EXAMPLE 4 Preparation of 5-amino-3-cyano-142.6-dichloro-4-trifluoromethylphenyl)-4-trifuoromethylthio pyrazole

A mixture of 1-(2,6-dichloro-4-trifluoromethylphenylhydrazono)1,2-dicyano-2-trifluoromethylthio ethane (144 mg; 0.34 mmol), preparedaccording to Example 3, copper (II) chloride (97 mg; 0.71 mmol), and 4ml of chlorobezene was stirred for 4 hours at 100° C. The solvent wasthen evaporated under vacuum The residue was dissolved in CH2CL2 and thesolution was washed by an aqueous solution of 1% ammonia in water. Theproduct was dried over sodium sulphate, and solvent was evaporated underreduced pressure. Purification by flash chromatography on silica gel andcrystallization from dichloromethane/hexane gave a white solid (105 mg;73% yield). The product was then recrystallized in a hexane/toluenemixture to provide a light brown powder (93 mg; 65% yield), meltingpoint 163° C. A second recrystalization provided a white powder of thetitle product with a melting point 165° C.

1. A process for the preparation of compound (III) which comprises thereaction between a compound of general formula (V) and dicyano acetylene(IV), said reaction carried out in the presence of water

wherein R is selected from CF₃, or C₁ to C₆ alkyl and M is an alkalineor alkaline-earth metal or silver.
 2. A process as claimed in claim 1wherein R is CF₃ and M is silver.
 3. A process as claimed in claim 1carried out in the presence of an organic solvent which is miscible withwater.
 4. A process as claimed in claim 3 in which the solvent isacetone or tetrahydrofuran.
 5. A process as claimed in claim 1 carriedout at a temperature of from −100 to +50° C.
 6. A process as claimed inclaim 1 carried out wherein the molar ratio of dicyano acetylene to thecompound of formula (V) is from 5:1 to 1:5.
 7. A process as claimed inclaim 2 carried out in the presence of an organic solvent which ismiscible with water.